Modeling the Human Bone-Tumor Niche: Reducing and Replacing the Need for Animal Data.

Srinivasa R Rao,James R Edwards,Claire M Edwards

doi:10.1002/jbm4.10356

Abstract

ABSTRACTBone is the most common site for cancer metastasis. Understanding the interactions within the complex, heterogeneous bone–tumor microenvironment is essential for the development of new therapeutics. Various animal models of tumor‐induced bone disease are routinely used to provide valuable information on the relationship between cancer cells and the skeleton. However, new model systems exist that offer an alternative approach to the use of animals and might more accurately reveal the cellular interactions occurring within the human bone–tumor niche. This review highlights replacement models that mimic the bone microenvironment and where cancer metastases and tumor growth might be assessed alongside bone turnover. Such culture models include the use of calcified regions of animal tissue and scaffolds made from bone mineral hydroxyapatite, synthetic polymers that can be manipulated during manufacture to create structures resembling trabecular bone surfaces, gel composites that can be modified for stiffness and porosity to resemble conditions in the tumor–bone microenvironment. Possibly the most accurate model system involves the use of fresh human bone samples, which can be cultured ex vivo in the presence of human tumor cells and demonstrate similar cancer cell–bone cell interactions as described in vivo. In addition, the use of mathematical modeling and computational biology approaches provide an alternative to preliminary animal testing. The use of such models offers the capacity to mimic significant elements of the human bone–tumor environment, and complement, refine, or replace the use of preclinical models. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Highlights

Bone is the most common site for tumor metastasis, in prostate cancers where approximately 70% of patients dying of these cancers show evidence of metastatic bone disease postmortem
Our previous work and that of others, has shown that tumor cells interact directly with cells of the bone environment in models of cancer–bone disease, which can be visualized and quantified histologically to assess the effects of drug treatment upon the bone–tumor niche.[4,6] the volume of bone destruction can be accurately determined by high-resolution μCT scanning, overall tumor volume assessed by soluble tumorderived factors released into the serum, and through the visualization of fluorescently tagged cancer cells
Well-established key events that occur during the tumor metastasis/bone remodeling process have been used in attempts to combine the computational modeling of both the bone and tumor environments to accurately predict interactions within the cancer– bone niche. This phenomenon has been modeled in multiple myeloma-induced bone disease, by focusing on the inhibition of osteoblasts and activation of osteoclasts.[54] mathematical modeling has shown that myeloma cells in the bone microenvironment set-off unstable oscillations of osteoblast and osteoclast numbers, leading to increased bone destruction.[55]. The dynamics of the tumor cell-induced vicious cycle can be incorporated in a mathematical model of prostate cancer–bone metastasis. This includes the modeling of bone as a reservoir of latent TGF-β that is released and activated during tumor-induced osteolysis, which in turn impacts the osteoblast:osteoclast balance in the remodeling unit.[56]. In addition, the role of cancer-associated fibroblasts[57] and immune cells[58] in tumor cell metastasis has been modeled, which is of particular interest given the diverse cellular environment of the bone metastatic niche

Summary

Introduction

Bone is the most common site for tumor metastasis, in prostate cancers where approximately 70% of patients dying of these cancers show evidence of metastatic bone disease postmortem.

Results

Conclusion